Group II metabotropic glutamate receptor antagonists LY341495 and LY366457 increase locomotor activity in mice

The group II metabotropic glutamate receptor (mGluR) antagonists LY341495 and LY366457 were profiled for their effects on locomotor activity in mice. Both compounds significantly increased locomotor activity. Observational studies showed that rearing was also selectively increased. LY366457-induced hyperactivity was significantly attenuated by the selective D1 dopamine receptor antagonist SCH23390 and also by the D2 dopamine receptor antagonist haloperidol but only at doses that significantly suppressed spontaneous locomotion. The selective 5-HT(2A) antagonist MDL100907 had no effect on LY366457-induced hyperactivity, while the less selective 5-HT(2A-C) antagonist ritanserin had only a modest effect. In all cases, the doses of antagonists that reduced the locomotor response to LY366457 were greater than those previously shown to reduce the locomotor response to the psychostimulants amphetamine and cocaine and MK-801. Pretreatment with reserpine also significantly attenuated the response to LY366457, possibly implicating a monoaminergic substrate in the mediation of this effect. The phenomenonology and pharmacology of the locomotor activation induced by the mGluR antagonists differs markedly from that induced by locomotor stimulants such as amphetamine, cocaine or MK-801. These results suggest that group II mGluRs may be involved in the tonic suppression of locomotor and exploratory activity, and this suppression can be disinhibited in the presence of a group II mGluR antagonist.